Nitric oxide, endothelium derived relaxing factor, has been implicated in the hypotension of septic shock. Notably, approximately 50% of patients dying of septic shock, succumb to refractory hypotension.In these investigations, we are studying the therapeutic value of nitric oxide synthase inhibition by serially following cardiopulmonary function, laboratory parameters and survival in an awake canine model of septic shock. Antagonists of the nitric oxide pathway may prove useful in the treatment of septic shock and the above studies are being conducted to investigate this possibility. This investigation may lead to therapeutic trials in patients with this highly lethal syndrome. Initial experiments in endotoxin challenged canines with Nomega-amino- L-arginine (J Exp Med, 1992) and Nomega-methyl-L-arginine (submitted, 1994) have revealed unexpected toxicities and some limitations to this approach. In the next study in the series, lower doses of a nitric oxide synthase inhibitor will be used with and without a conventional vasopressor (epinephrine) to better simulate the clinical conditions under which these agents are likely to be used. Further, the inhibitor will be used in an E. coli peritonitis model of septic shock to access the effects of these agents in actual infections. Nitric oxide synthase inhibitors that are highly selective for the induced isoform of this enzyme (the isoform implicated in septic shock) are being sought for future studies.